Project Summary/Abstract: Advanced cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) have very poor survival due to limited effective treatments. Three major obstacles have stalled drug development: 1) the low number of patients with each T-cell lymphoma (TCL) subtype, which limits sample availability and clinical trial enrollment; 2) genetic and tissue microenvironment variability across subtypes; and 3) a lack of cellular and animal models to test immunotherapies. Thus, there is a major scientific gap in the development of new treatments for TCL. Here, we propose the use of an innovative implantable microdevice (MD), smaller than a grain of rice, that is placed directly into a patient's cancerous lesion to screen drugs and to identify the most effective cancer drug to treat TCL on a personalized level. Our MD delivers up to 20 drugs of any class into non-overlapping regions of a tumor. It is delivered into the skin with a small needle and retrieved in 3 days by excising the device along with a few millimeters of surrounding cancer tissue with a standard skin biopsy tool. This device allows testing drugs directly inside the living tumor with microdoses, thereby avoiding the risk of systemic side effects. Drug sensitivity is determined by histologic assessment of the tumor surrounding the device. The MD and the method for processing and analyzing tissue has been validated across multiple cancer types in mouse models and is being evaluated in an ongoing pilot study in breast cancer. The specific aims of these studies will be to: i) determine the safety and feasibility of implanting and retrieving the MD in skin lesions of TCL; ii) assess local responsiveness of TCL to cancer treatments delivered via the MD through microscopic assessments using highly multiplexed cyclic immunofluorescence, a novel platform capable of characterizing subcellular changes in the native immune microenvironment following drug treatment with over 30 markers, and iii) correlate genetic abnormalities of TCL with drug response to identify potential biomarkers of response and to determine if the MD can be used to predict clinical response by correlating the local tissue response to drug with a patient's clinical response to the same drug when given systemically. We hypothesize that in situ tissue profiling of drugs in TCL can predict systemic responses to standard of care therapies and therefore can serve as a rapid screen for multiple investigational single or combination treatments. Additionally, genomic and immunophenotypic analysis of tumors may assist in identification of predictive biomarkers of treatment. The results of our studies will focus clinical trial efforts toward the most promising treatment strategies and usher in the era of precision medicine in TCL.